The research program outlined herein is directed toward the design of general strategies for the syntheses of oxygenated natural and unnatural products that possess significant biological activity. On the methodological front, further applications of the dipolar cycloadditions of nitrile oxides will be developed, and extensions of our strategy exploiting furans and hydropyrans as key intermediates for the asymmetric syntheses of natural products and selected skeletal subunits will be broadly extended. New methods for functionalization of hydropyrans will be investigated. We will also explore some unique strategies for effecting macrolactonizations of glycosylated, seco-acid derivatives of macrolide antibiotics. A variety of novel techniques for the asymmetric syntheses of cyclopropanes and for the stereoselective construction of trisubstituted double bonds will also be explored. The synthetic objectives include the: (1) completion of the total syntheses of the erythromycins A and B by a novel strategy that features macrolactonization of a glycosylated seco-acid derivative; (2) design and preparation of analogues of erythromycins A and B, including substances that contain the essential pharmacophore of the natural antibiotics on a molecular framework unrelated to that of the macrolide backbone, in an effort to prepare novel, orally-active antibiotics; (3) completion of the total synthesis of breynogenin, the aglycone of breynins A and B, which are unusual sulfur containing glycosides that exhibit significant hypocholesterolemic activity; (4) total synthesis of the polyhydroxylated alkaloid castanospermine, a potent inhibitor of alpha-glycosidase I, employing a strategy that may be readily modified to access selected related derivatives as potential drug candidates for the treatment of AIDS; (5) design and development of a unified synthetic approach to octosyl acid A and the closely related ezomycins A1 and A2, which exhibit antifungal and antibiotic activity; and (6) total synthesis of the antifungal antibiotic ambruticin employing a convergent strategy that exploits useful extensions of the furan methodology together with the development of novel techniques for the asymmetric synthesis of 1,2,3-trisubstituted cyclopropanes as well as for the stereoselective synthesis of trisubstituted olefins. Quantities of the targeted compounds and selected congeners will be prepared for submission to C.P. Starks, Inc., Eli Lilly Company, DuPont, Merck, and Abbott Laboratories for biological evaluation.